Pathogenesis and treatment of endometriosis: A systemic literature review

Endometriosis is a chronic gynecological disorder characterized by the abnormal growth of endometrial - like tissue outside the uterine cavity, leading to inflammation, pelvic pain, infertility, menstrual irregularities, and significant deterioration in the quality of life among affected women . Despite decades of clinical investigation, the exact pathogenesis of endometriosis remains incompletely understood due to its multifactorial nature involving hormonal imbalance, immune dysfunction, genetic s usceptibility, inflammatory responses, environmental exposure, and altered cellular signaling mechanisms . This systematic literature review critically examines the current understanding of the biological mechanisms responsible for the initiation and progre ssion of endometriosis while simultaneously evaluating contemporary therapeutic approaches used in its management . The review synthesizes evidence from recent clinical studies, experimental investigations, epidemiological analyses, and molecular research t o identify the major pathogenic pathways associated with the disease . Findings from the literature indicate that retrograde menstruation alone cannot fully explain the development of endometriosis, and increasing evidence supports the combined role of estr ogen dependency, chronic inflammatory activation, oxidative stress, angiogenesis, immune escape mechanisms, and epigenetic alterations in disease progression . The review further highlights the contribution of cytokines, growth factors, and abnormal immune cell activity in facilitating ectopic implantation and survival of endometrial tissues . In terms of treatment, the study evaluates both medical and surgical management strategies, including hormonal therapy, nonsteroidal anti - inflammatory drugs, gonadotrop in-releasing hormone agonists, laparoscopic interventions, fertility - preserving approaches, and emerging targeted molecular therapies . The analysis reveals that although current treatments provide symptomatic relief and temporary disease suppression, recur rence rates remain considerably high, and long -term therapeutic outcomes continue to present clinical challenges . Furthermore, delays in diagnosis, variability in symptom presentation, and limitations in noninvasive diagnostic techniques significantly affe ct early disease management and patient prognosis . The review concludes that effective management of endometriosis requires an integrated multidisciplinary approach combining early diagnosis, personalized treatment planning, continuous monitoring, and advanced research into molecular-targeted therapies capable of improving long -term reproductive and clinical outcomes . The study emphasizes the urgent need for further translational research to better understand disease mechanisms and develop safer, more effec tive, and patient -centered therapeutic strategies for endometriosis management.

Endometriosis, Pathogenesis, Hormonal Therapy, Inflammation, Gynecological Disorders

Endometriosis is characterized by the existence of endometrial glands and stroma outside the uterine cavity , primarily, but not only , inside the pelvic region . It is a chronic inflammatory disease dependent on estrogen , affecting women during their period of reproduction , and is linked to pelvic pain and infertility [1]. The incidence of endometriosis is around 5% , especially between the ages of 25 and 35 . A 0 . 1% yearly incidence of endometriosis has been found among women aged 15 to 49 years . The condition appears prevalent among adolescent females experiencing chronic pelvic pain [2]. Around 10% of women of reproductive age suffer with endometriosis, with over one third experiencing infertility , approximately twice the incidence rate among women without the condition [3]. As many as 50% of infertil e women are diagnosed with endometriosis [4]. It progresses during menstrual cycles and affects many organs , leading to localized gynecologic lesions and systemic inflammatory conditions [5]. Lesions can be categorically classified as peritoneal/superficial implants , ovarian endometriotic cysts/endometriomas, deep endometriosis, and extra-abdominal localizations. Endometriosis is International Journal of Clinical Obstetrics and Gynaecology https://www.gynaecologyjournal.com ~ 883 ~ linked to painful manifestations , including chronic pelvic pain , dysmenorrhea, dyspareunia, infertility, reduced sexual function , and psychological distress [6]. Moreover, asymptomatic endometriotic lesions can be identified in about fifty percent of women undergoing infertility treatment [7]. Due to ongoing inflammation and immunological dysregulation , women with endometriosis have an elevated risk of cardiovascular disease , rheumatoid arthritis , asthma, melanoma, ovarian cancer , and breast cancer [8]. The main aim of the present systematic review was to critically review and evaluate the mechanism behind endometriosis and treatments to alleviate the pain and infertility in women with endometriosis.

Present systemic literature review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement . Studies were identified by searching the google scholar, PubMed databases. In addition, the

of all selected articles were searched . Studies published in English were considered . Keywords for literature search for treatment section used was (("therapeutics" [MeSH Terms]. OR "therapeutics" [All Fields ]. OR "treatments" [All Fields]. OR "therapy" [MeSH Subheading]. OR "therapy" [All Fields]. OR "treatment" [All Fields ]. OR "treatment s" [All Fields].) AND ("endometriosis" [MeSH Terms ]. OR "endometriosis" [All Fields]. OR "endometrioses" [All Fields].)) and for pathogenesis section was ("etiology" [MeSH Subheading]. OR "etiology" [All Fields]. OR "pathogenesis" [All Fields ].) AND ("endometriosis" [MeSH Terms]. OR "endometriosis" [All Fields ]. OR "endometrioses" [All Fields].). Inclusion/exclusion criteria Studies for pathogenesis section were included if involving any mechanism for endometriosis related pain or infertility . For treatment section only studies were involved in which patients suffering from endometriosis, reported outcome were pain relief, symptom relief (dysmenorrhea, dyspareunia), pregnancy rate, live birth rate , conception rate, fecundity rate . Studies which were review paper , case reports , editorials, commentary, systemic review, metanalysis, non-English articles and in which patients were suffering from other serious fetal disease like cancer, chronic heart disease, HIV were excluded. Search using the specific keywords generated 39048 records without duplicates. Potential studies were selected via their title and abstract . Of these , 7254 were excluded after reading the content of the abstracts and titles , and 3 8 met the inclusion criteria and were selected for systemic review . The initial search was performed by two independent author ……… . , who assessed the eligibility criteria independently and in a masked manner. There were no discrepancies between the authors. Records identified from databases: PubMed (n=37079) Google scholar (n= 5980) Registers (n = ) Records removed before screening: Duplicate and non-English records removed (n = 4011) Records screened (n = 39048) Records excluded review paper, case reports, editorials, revies, systemic reviews, metanalysis, commentary. (n = 31755 ) Reports assessed for eligibility based on abstract and title (n = 7293) Reports excluded not following inclusion criteria Studies included in the review (n = 38) Identification of studies via databases and registers Identification Screening Included Pathogenesis of endometriosis Understanding the pathogenesis of endometriosis is crucial . None of the proposed theories have been able to comprehensively explain the natural history of the disease and its associated diverse clinical presentations [4]. Common mechanism lies is dysregulated hormonal signaling , enhanced proinflammatory microenvironment that has the potential to drive the initiation , maintenance, and progression of the disease International Journal of Clinical Obstetrics and Gynaecology https://www.gynaecologyjournal.com ~ 884 ~ [4]. Among the existing theories following stand out and could explain the origin and progression of endometriosis. Retrograde menstruation theory Retrograde menstruation based theory is the most commonly accepted a nd washypothesized by Sampson in 1927 [9]. Functional endometrial tissue translocate into the pelvic cavity via the fallopian tubes during menstruation, adheres to peritoneal mesothelial cells , proliferates, and ultimately invades pelvic structures. As per Kruitwagen RFPM et al . , refluxed endometrial cells may migrate to the right hypochondrium via the clockwise peritoneal fluid flow and are likely to implant more readily on the right diaphragmatic leaf due to entrapment by the falciform ligament . The observed prevalence of ri ght- sided endometriotic implants in 90% of patients corroborates the menstrual reflux theory [10]. Early age at menarche , prolonged duration and heavy menstrual flow are all well -known epidemiological risk factors for developing endometriosis. The anatomical prevalence of endometriosis on the right side of both hemipelvis and diaphragm further substantiates this theory [11]. Coelomic metaplasia and mullerian remnants hypotheses Endometriotic lesions arise in situ from embryological remains or via metaplasia . According to the mullerian remnants theory , [12] endometriosis results from the abnormal migration and differentiation of embryonic cell remnants derived from the Mullerian ducts during organogenesis . This concept elucidates the occurrence of endometriosis in adolescents prior to or shortly post menarche, as well as in fetuses. As Signorile PG et al. have observed the dislocation of primitive endometrial tissue outside the uterine cavity during organogenesis . Such e mbryological research studies [13] substantiate the existence of Mullerian remains in the cul -de-sac region , uterosacral ligaments , and medial wide ligaments. Hematogenous and lymphovascular dissemination According to this hypothesis , endometrial cells ent er to ectopic regions after entering the uterine lymphatic or vasculature after menstruation. Sampson JA . et al . observed the presence of endometrial tissue in the uterine vasculature [14] and Mechsner S et al . detected the emboli in sentinel lymph nodes [15]. Endometriosis-derived cells can migrate and micrometastasize to various extra-pelvic organs, such as the brain , liver, spleen, and lung, in mouse models of surgically induced endometriosis [16]. Stem cell theory: Abnormal stem cell trafficking contributes to the etiology and pathophysiology of endometriosis [17]. Subsequent research has validated the contribution of bone marrow to the endometrium [18, 19]. Taylor et al . observed thatendometrial cells originating from donors were found in endometrial biopsy specimens from all bone marrow recipients , comprising 0. 2% to 48% of epithelial cells and 0. 3% to 52% of stromal cells . Thus, BMDSCs traverse the circulatory system and contribute to the composition of eutopic endometrium. After their migration to the endometrium , these BMDSCs may become confined to an endometrial cell lineage [17]. Genetic etiology: No definitive inheritance pattern has been identified; nonetheless , familial clusters of endometriosis have been observed in humans . A recent cross -sectional study by Bianco et al. involving 213 infertile women with endometriosis who underwent IVF procedures revealed that single nucleotide variants of FSHB and FSHR independently affected the hormonal profile (both FSH and LH levels) and consequently influenced the number of oocytes collected at any stage of the disease [20]. Table 1: Different theories for pathogenesis of endometriosis S. No. Theory for pathogenesis of endometriosis Key concept 1. Retrograde menstruation theory Functional endometrial tissue translocate into the pelvic cavity via the fallopian tubes during menstruation, adheres to peritoneal mesothelial cells, proliferates, and ultimately invades pelvic structures 2. Coelomic metaplasia and mullerian remnants hypotheses Endometriotic lesions arise in situ from embryological remains or via metaplasia. 3. Hematogenous and lymphovascular dissemination Endometrial cells enter to ectopic regions after entering the uterine lymphatic or vasculature after menstruation 4. Stem cell theory Abnormal stem cell trafficking contributes to the etiology and pathophysiology of endometriosis. BMDSCs traverse the circulatory system and contribute to the composition of eutopic endometrium. 5. Genetic etiology Single nucleotide variants affects the hormonal profile and influence the no of oocyts. Mechanisms of endometriosis associated infertility: Although there is a clinically established correlation between endometriosis and infertility , the mechanisms involved in endometriosis-related infertility remain ambiguous , and this disorder is presently considered highly complex. Role of pain: When superficial dyspareunia (pain in or around the vaginal introitus) makes intercourse difficult to attain or deep dyspareunia makes intercourse difficult to sustain , resulting in avoidance of sexual activity, pain may be a contributing factor to infertility caused by endometriosis . The disease-related chronic, non-menstrual pelvic pain may affect sexual life by decreasing arousal, orgasm, frequency of sexual activity , and desire . Intimate relationships , emotional health , and overall quality of life will all suffer greatly as a result [4]. One cross-sectional study including 300 women with histologically diagnosed endometriosis by Kj W et al. demonstrated that the severity of superficial dyspareunia was correlated with increased chances of infertility issues [21]. Mechanical factors Anatomical abnormalities and mechanical factors may interfere with oocyte release from the ovary , obstruct tubal ovum pickup or transport , and/or impede sperm transfer into the fallopian tube. In an in vivo study including 21 cynomolgus monkeys, The impaired fertility appeared to be mediated primarily by failure of follicular rupture and/or pelvic adhesions [22]. Declined Ovarian reserve: Increasing molecular , histological, and morphological data indicates that endometriomas adversely affect ovarian function. An endometrioma is a distinctive benign cyst lacking a true capsule , resulting in the interchange of cystic International Journal of Clinical Obstetrics and Gynaecology https://www.gynaecologyjournal.com ~ 885 ~ contents with the neighboring healthy ovarian cortex . The discharge of toxic cyst contents into the surrounding ovarian parenchyma may result in oxidative stress , fibrosis, depletion of cortical stroma , smooth muscle cell meta plasia, compromised vascularization, and, subsequently, diminished follicular maturation and atresia in early follicles [4]. A histopathological investigation showed increased fibrotic tissue around endometriomas compared to other benign cysts [23]. Oocyte quality , embryo transport , sperm function and motility, sperm-oocyte interaction The inflammatory effects caused by endometriomas have been demonstrated to influence both egg production and ovulation in the affected ovary [24]. The functional quality of sperm is diminished, maybe due to the inflammatory and toxic effects of peritoneal fluid and elevated levels of activated macrophages [25]. Leyendecker G et al. demonstrated that the transport of gametes is i nfluenced by the inflammatory milieu , anatomical abnormalities, and uterotubal dysperistalsis linked to endometriosis [26]. Effect on Implantation: Impaired implantation may result from diminished endometrial receptivity or decidualization ability in these patients. The functional dysregulation of steroid hormone signaling in endometriosis, including the increase of E2 -induced cell proliferation , inflammation, and progesterone resistance , appears to significantly reduce endometrial receptivity in these individuals [27]. Taylor et al. observed that reduced expression of implantation-related genes HOXA10 and HOXA11 has been implicated with compromised endometrial receptivity, leading to decreased implantation rates [28]. Mechanism of Chronic Pelvic Pain in Endometriosis Multiple processes may underlie pain in individuals with endometriosis; understanding these mechanisms may assist healthcare professionals in elucidating the nature of the pain symptoms and determining appropriate therapies for endometriosis-related pain. Inflammation: Endometriotic lesions and the peritoneal fluid of individuals with endometriosis exhibit increased levels of inflammatory cells , cytokines, and chemokines , culminating in an inflammatory environment . Macrophages, mast cells , and neutrophils, together with other inflammatory cells , are activated, resulting in increased production of various inflammatory mediators, including interleukins (IL) such as IL - 1β, IL-37, and IL -6; tumor necrosis factor (TNF) -α; nerve growth factor (NGF); and pain -associated molecules like prostaglandin, substance P , and glycodelin . Cytokines, chemokines, and inflammatory mediators linked with inflammation can affect inflammatory cells , increasing their recruitment [29]. This detrimental cycle may accelerate the proliferation and invasion of endometriotic lesions, resulting in a chronic inflammatory microenvironment and thus , chronic pelvic pain [29]. Tamburro S et al . found that the severity of dysmenorrhea is also correlated with elevated levels of TGF -β1 [30]. Mast cells participate in neuropathic pain by directly sensitizing or activating primary nociceptive neurons through mediators like histamine and leukotriene . The number of mast cells and activated mast cells is elevated in endometriosis , particularly in cases of deep-infiltrating endometriosis [31]. Nerve fibres in endometriotic lesions: The abnormal innervation of endometriotic lesions is considered crucial in the etiology of chronic pelvic pain in patients with endometriosis [32]. Mechsner et al and Arnold J et al reported that the number of nerve fibers , including Aγ sensory, C sensory , cholinergic, and adrenergic types , is found to be elevated in peritoneal endometrial tissue relative to healthy peritoneum [33, 34]. McKinnon B et al . revealed that peritoneal fluid from individuals with endometriosis enhanced the emergence of sensory neurites from the dorsal root ganglia [34]. Women with endometriosis exhibiting elevated pain scores for dysmenorrhea and pelvic pain had substantially increased levels of neuronal markers (neurofilament and protein gene product) , and severe dysmenorrhea had a positive association with nerve fibers relating to endometriosis [34, 35]. Kajitani et al . observed that elevated NGFs in endometriosis patients correlated with a higher density of nerve supply , which was associated with intense pain [36]. Endometriosis and Peripheral Sensitization: Peripheral sensitization is a process that elucidates the continued pain in the absence of lesions [37]. Anaf et al. have found perineural invasion in individuals with endometriosis [38]. Endometriosis and Central Sensitization: Central sensitization may also arise from changes in cerebral activity or structure . Changes in brain activity in women with chronic pain have been examined using functional magnetic resonance imaging and positron emission tomography . Women with dysmenorrhea exhibited higher sensitivity to painful thermal stimuli in comparison to women without dysmenorrhea [38, 39]. As-Sanie S et al . demonstrated that Women experiencing endometriosis - related pain had enhanced resting connectivity between the anterior insula , the principal region for pain processing , and other brain areas, in contrast to healthy controls or endometriosis patients devoid of pain . Women suf fering from painful endometriosis had elevated levels of excitatory neurotransmitters in the anterior insula in comparison to the other two control groups. Elevations in neurotransmitters correlated with a link between the anterior insula and the medial pr efrontal cortex, a region involved in pain modulation [40]. An central sensitization assessment tool indicated that over 40% of patients with endometriosis had central sensitization [41]. Cross Sensitization: Cross-organ sensitization refers to the phenomenon when pain in one visceral organ stimula tes the sensitivity to pain in another organ [42]. Women with endometriosis experience a co -occurrence of bladder pain syndrome, characterized by bladder pain accompanied by urine symptoms such as urgency and frequency [43]. The precise process of cross -sensitization remains unidentified . Visceral afferents from the uterus, bladder, and colon converge at a same place in the spinal cord , therefore sensitizing neighboring cells due to their spatial proximity [44, 45]. Dichotomizing afferents , which are individual peripheral neuronal cell bodies capable of producing several axons to simultaneously innervate various abdominal organs , are proposed as a mechanism for cross -sensitization [46, 47]. Phan et al. observed that women suffering from endometriosis -related chronic pelvic pain frequently exhibit myofascial dysfunction and sensitization expanding beyond the pelvic area , potentially triggered or sustained by chronic pelvic floor spasms [48]. Psychosocial Factors: The severity of pain can be influenced by psychological factor s like depression , anxiety, pain catastrophizing, pain expectation , and focus on pain [49, 50]. International Journal of Clinical Obstetrics and Gynaecology https://www.gynaecologyjournal.com ~ 886 ~ Although the actual mechanism connecting psychological variables to endometriosis -related chronic pain remains unidentified, Furthermore, van Aken MAW et al . found that women with endometriosis had markedly elevated pain catastrophizing scores [51]. Table 2: Mechanism behind pathogenesis of endometriosis Mechanisms of endometriosis associated infertility S. No. Mechanism Key concept 1. Role of pain Pain in or around the vaginal introitus during intercourse, non-menstrual pelvic pain may affect sexual life thus may be a contributing factor to infertility. 2. Mechanical factors Anatomical abnormalities and mechanical factors may interfere with oocyte release from the ovary, obstruct tubal ovum pickup or transport, and/or impede sperm transfer into the fallopian tube. 3. Declined Ovarian reserve The discharge of endometriomas contents into the surrounding ovarian parenchyma may

in oxidative stress, fibrosis, depletion of cortical stroma, smooth muscle cell metaplasia, compromised vascularization, and, subsequently, diminished follicular maturation and atresia in early follicles. 4. Oocyte quality, embryo transport, sperm function and motility, sperm-oocyte interaction The inflammatory effects caused by endometriomas have been demonstrated to influence egg production and ovulation, quality of sperm. 5. Effect on Implantation Due to diminished endometrial receptivity or decidualization Impaired implantation may

in infertility issues. Mechanism of Chronic Pelvic Pain in Endometriosis S. No. Mechanism Key concept 1. Inflammation Endometriotic lesions and the peritoneal fluid of individuals with endometriosis exhibit increased concentrations of inflammatory cells, cytokines, and chemokines, establishing chronic inflammatory milieu that promotes lesion progression and chronic pelvic pain. 2. Nerve fibres in endometriotic lesions The abnormal innervation of endometriotic lesions is considered crucial in the etiology of chronic pelvic pain in patients with endometriosis. 3. Endometriosis and Peripheral sensitization Perineural invasion elucidates the continued pain in endometriosis. 4. Endometriosis and Central Sensitization Central sensitization may also arise from changes in cerebral activity or structure. Changes in brain activity in women with chronic pain, 5. Cross Sensitization Sensitization expanding beyond the pelvic area in women suffering from endometriosis- related chronic pelvic pain, 6. Psychosocial Factors The severity of pain can be influenced by psychological factors like depression, anxiety, pain catastrophizing, pain expectation, and focus on pain. Diagnosis Diagnosing endometriosis necessitates a comprehensive set of tools encompassing clinical evaluation , biological indicators , and techniques for imaging , including non-invasive procedures like ultrasonography and invasive methods for visual inspection . Assessing symptomatology and conducting a physical examination are the initial steps in diagnosing endometriosis [52, 53]. A physical examination suggests a diagnosis of endometriosis when multiple criteria are fulfilled , including palpable nodularity and atypical pelvic anatomy , particularly in the vagina, rectovaginal space, pouch of Douglas , rectosigmoid region, and posterior wall of the urinary bladder [52-54]. Additional signs, including tenderness, reduced mobility, and a retroverted uterus , as observed during palpation , may also suggest the presence of endometriosis [55]. Various potential biomarkers including inflammatory cytokines [56]. , growth factors [57]. , angiogenesis markers [58]. , stem cell markers [58]. as well as tissue matrix metalloproteinases and adhesion molecules have been investigated for laboratory testing [59]. butnone have demonstrated sufficient reliability as diagnostic tools. Ultrasonography is a cost -effective, readily accessible, and non- invasive imaging technique for evaluating endometriosis , employing transabdominal, transvaginal, or transrectal methods. It is commonly employed as an initial screening test for endometriosis and as a preoperative tool for assessing the extent of surgical procedures [60]. At present , transvaginal ultrasonography is preferred technique for detecting ovarian endometriomas, with good sensitivity (93%) and specificity (97%) when performed by an experienced practiti oner [61]. Magnetic resonance imaging (MRI) is increasingly employed for assessing patients with e ndometriosis, serving as a supplementary technique to transvaginal ultrasonography , especially when the physician suspects the existence of deep infiltrative lesions [62]. Surgical exploration is an invasive visualization method employed specifically to get qualitative evaluation data regarding the actual extent of endometriotic lesions. Despite the array of imaging techniques , laparoscopic examination coupled with histological examination remains the absolute standard for the confirming diagnosis of endometriosis [63]. Treatment of endometriosis: The selection of treatment will be based upon the severity of symptoms, the degree and location of the disease , the desire for p regnancy, and the patient's age . It may involve pharmacological treatment, surgical intervention, or a combination of both approaches . Pharmacological treatment for endometriosis seeks to alleviate symptoms or avert recurrence of postsurgical disease [64]. Management of endometriosis associated pain Considering the substantial number of inappropriately treated patients, multi modal treatment is the need of the hour and it is imperative for gynecologists in private practice to familiarize themselves with multimodal therapy principles , as they serve as the primary point of contact for their patients [65]. Pharmacologic management of endometriosis associated pain: Main objective of pharmacological treatment for endometriosis is to alleviate symptoms or avert recurrence of postsurgical disease. Certain pharmaceuticals induce conditions like hyperprogestogenic treatment, which includes combination oral contraceptives and progestins . These medications are the International Journal of Clinical Obstetrics and Gynaecology https://www.gynaecologyjournal.com ~ 887 ~ primary option; they function by suppressing ovulation, inducing decidualization, and leading to a reduction in lesion size . Hypoestrogenic therapy , utilizing Gonadotropin -Releasing Hormone (GnRH) agonists , constitutes the secondary therapeutic option for this condition . It is an efficacious medication for women who are unresponsive to combination oral contraceptives or progestins . They are not provided orally due to degradation during digestion; thus , their administration is advised via parenteral, subcutaneous, intramuscular, nasal spray, or intravaginal routes [64]. Muzii et al. found that the use of dienogest in medical treatment markedly decreases the diameter of endometriom as and alleviates associated pain , while maintaining ovarian reserve , evidenced by a notable enhancement in antral follicle count (AFC) and no significant alteration in anti -Müllerian hormone (AMH) levels [66]. When the effects of dienogest and Norethindrone acetate in symptomatic women with ovarian endometriomas were compared by et al . then a reduction in ovarian endometrioma size was observed during treatment in both groups , with no significant differences between groups dienogest and Norethindrone acetate . Even Progestin treatment utilizing dienogest and Norethindrone acetate demonstrates efficacy alleviating associated symptoms , with dienogest exhibiting superior symptom ( dysmenorrhea, dyspareunia, chronic pelvic pain) relief and enhanced tolerability among women [67]. Another multi centric case control study by Angioni S et al . also demonstrated a significant decrease in the pain while treating the ovarian endometriomas patients with dienogest [68]. As per Bergqvist et al. two months of triptorelin treatment has been found to be efficacious in reducing the pain symptoms in laparoscopically verified endometriosis patients . The reduction of endometriotic l esions was 50% with triptorelin therapy, a much greater degree than that observed with placebo [69]. By blocking the release of GnRH and the peak of luteinizing hormone (LH), hyperandrogenic therapy (danazol or gestrinone) creates a pseudomenopause by raising levels of androgen hormones (free testosterone) and lowering levels of estrogen (inhibits ovarian production) , which results in endometriotic implant atrophy [64]. This group of drugs is unsuitable for extended use mostly owing to androgenic effects , including seborrhea, hypertrichosis, weight gain, adverse effects on serum lipoprotein cholesterol distribution , decreased HDL levels , and increased LDL levels [64]. Non-drug management of endometriosis associated pain: Considering side effects associated with pharmacological treatments, such as menopausal disorders , other non -drug therapies may serve as complement or alternatives for medical treatment of endometriosis patients . Acupuncture's ability to reduce pain has bee n linked to a few physiological and psychological mechanisms [70]. Sousa et al observed a decrease in visual analogue scale (VAS) scores for chronic pelvic pain and dyspareunia in the endometriosis patients who received acupuncture therapy than placebo. Two months post-therapy, the findings were sustained only in the experimental group . In the view of quality of life , they observed an improvement in all evaluated measures , however statistical significance was achieved just in the experimental group [71]. Physical activity and exercises also have been utilized over three decades ago for the treatment of symptoms related with endometriosis [72]. A primary mechanism via which physical activity confers beneficial health effects is its ability to diminish chronic low -grade inflammation [73]. The amount of IL -6 released is dependent upon the mass of muscle recruited , the intensity and duration of the exercise and is related (inversely) to the glycogen status of the muscles [73]. Goncalves et al . demonstrated that in women with endometriosis, yoga practice is found to improve their quality of life and a decrease in their levels of chronic pelvic pain [74]. Nutritional intervention also found to be effective in pain management in endometriosis patients. Marziali M et al . found that painful symptoms of endometriosis were decreased after 12 months of gluten free diet when provided during severe painful endometriosis [75]. Treatment of endometriosis associated infertility : In women with endometriosis, infertility mostly results from chronic pelvic inflammation. Adhesions resulting from this inflammatory process may impair pelvic anatomy , and local detrimental environment to conception can be established by inflammatory molecules [76]. Current treatment of endometriosis -associated infertility focuses on improving fecundity by rem oving or reducing ectopic endometrial implants and restoring normal pelvic anatomy [77]. Pharmacological treatment endometrio sis associated infertility: Pharmacological treatments for endometriosis encompass hormonal agents such as combination oral contraceptives, progestins, danazol, and gonadotropin -releasing hormone agonists or antagonists (GnRH analogs) . Hormonal medical therapy does not improve infertility in women with endometriosis. No advantages have been demonstrated in the management of infertility related with endometriosis. Shaw et al reported that goserelin depot and danazol treatment for endometriosis have shown no statistically significant difference between the groups in terms of percentage of pregnancies nor mean time to concept ion. Shaw 1992 Medical treatment should generally be avoided in individuals with endometriosis and subfertility seeking a live birth . The one exception to this regulation is to individuals undergoing in -vitro fertilization (IVF) [77]. Research indicates that extended administration of GnRH agonists prior to IVF or ICSI may enhance pregnancy outcomes in women with severe endometriosis . Guo et al reported that upon treatment with GnRH agonists combined with transvaginal ultrasound-guided cyst aspiration serum E2 levels , the quantity of ovarian follicles measuring 14 mm or more , the number of retrieved oocytes , the rate of high -quality embr yos, the implantation rate , and the clinical pregnancy rate were significantly elevated in the experimental group compared to the control group (all P < 0 . 05) [78, 79]. Like GnRHa, the use of oral contraceptives has demonstrated enhanced results when administered for 6 -8 weeks prior to ART . A randomize d controlled study conducted by de Ziegler et al. demonstrated that continuous use of oral contraceptive (OC) for 6 to 8 weeks before to assisted reproduction therapy (ART) have shown similar ART results to those of age -matched individuals without endometriosis [80]. Surgery: The surgical therapy options for endometriosis - associated infertility include laparotomy , laparoscopy, and robotic surgery . Laparoscopic intervention is predominantly employed owing to its benefits , such as reduced costs , hospitalization and faster recovery [81]. Marcoux et al . findings indicated that resection or ablation of minimal and mild endometriosis markedly improved fecundity in infertile women compared to diagnostic laparoscopy alone (cumulative probability, 30. 7% and 17 . 7%, respectively; P=0 . 006). The fecundity rates were 4 . 7 and 2 . 4 per 100 person months , International Journal of Clinical Obstetrics and Gynaecology https://www.gynaecologyjournal.com ~ 888 ~ respectively, and the absolute increase in the 36 -week chance of a pregnancy extending beyond 20 weeks due to surgery was 13 percent. No substantial difference was seen between excisional and ablative procedures [82]. Laparoscopic cystectomy of endometriomas emerged as a better choice than fenestration and coagulation because the former has been associated reduced recurrence of signs and symptoms , a decreased incidence of reoperation, and an elevated cumulative pregnancy rate compared to the latter [83, 84]. When comparison between cystectomy (group 1) and fenestration and coagulation (group 2) for the management of endometriomas was made by Alborzi et al. then it was found after two years , the recurrence of symptoms, including pelvic pain and dysmenorrhea, was 15. 8% in group 1 and 56 . 7% in group 2 . The reoperation rates were 5 . 8% in group 1 and 22 . 9% in group 2 , with these differences being statistically significant . The cumulative pregnancy rate during the 1 -year follow -up was mu ch greater in group 1 (59 . 4%) compared to group 2 (23 . 3%) [83]. Similar results were also reported by Beretta et al in their study [84]. Superovulation and Intraut erine Insemination: Numerous randomized controlled trials have demonstrated that ovulation induction and superovulation, both with and without intrauterine insemination (IUI) , enhance conception rates in people with normal anatomy and with minimal-mild endometriosis [85, 86]. As per Tummon et al study, superovulation and IUI was associated with superior live birth rate (14%) than no treatment (2%) in women with minimal or mild endometriosis [85]. A similar trial by Deaton et al indicated an advantage of clomiphene citrate and IUI over controls (fecundity 0. 095 vs. 0. 033) [87]. It is crucial to note that ovarian stimulation may worsen endometriosis; thus , it should be conducted in a regulated way and restricted to 3 -4 cycles [77]. In vitro Fertilization: Nowadays, IVF is the most effective treatment for infertile women suffering from endometriosis [88]. Despite its widespread application , the impact of endometriosis on conception rates following ART and the efficacy of ART therapies in women with endometriosis remain contentious concerns. As per Geber et al study patients with endometrioma undergoing IVF exhibited improved pregnancy outcome . The existence and severity of endometriosis do not affect IVF outcomes, and no evidence was found indicating a higher frequency of miscarriage [89]. Table 3: Treatment of endometriosis S. No. Study design Study population Treatment/ Dosage Outcomes and

Author, year 1. Prospective study 32 patients with unilateral endometrioma Medical treatment with dienogest significantly reduces endometrioma diameter (40%) reduction and improvement in Mean visual analog scale scoreassociated with pain ((0. 9 ± 1. 0, p < . 0001). Muzii et al. 2019 2. Retrospective study 135 symptomatic women with ultrasonographic diagnosis of ovarian endometrioma. Dinogest 2 mg/day and Norethindrone acetate 2. 5 mg/day The mean diameter of endometriomas was reduced by both Dinogest (D)-2. 51 mm at 6 months and -6. 54 mm at 12 months and Norethindrone acetate(N)-2. 94 mm at 6 months and -5. 80 mm at 12 months. A marked decrease in pain was significantly higher in group D than in group N just after 6 months (chronic pelvic pain P = 0. 002, dysmenorrhea P = 0. 001, dyspareunia P < 0. 001). Simona Del Forno et al. 2019 3. Prospectivemulticentric case control study 81 patients with ovarian endometriosis 2 mg of dienogest and cyclic oral estro-progestins (ethinyl estradiol 30 mcg [EE]. plus dienogest 2 mg) Dinogestcause a 75% volume reductionthe size of the endometrioma cysts. significant improvement in the mean visual analog scale score(19 ± 15, p < . 001, Dinogest). Angioni Set al. 2019 4. Prospective, randomized study 49 women with symptoms of laparoscopically verified endometriosis. 24 patients had active treatment and 25 received placebo. 3. 75 mg of triptorelin . The total pain score was significantly reduced in the triptorelin group. The mean difference of pain score between the baseline and 6 months of triptorelin treatment was 2. 85 (95%, CI 2. 23. 5). The average area of endometriotic lesions was reduced 45%. Bergqvist A et al. 1998 5. Prospective randomized trial 42 women who were on the waiting list to undergo a video laparoscopy Experimental treatment of acupuncture, and the other received placebo therapy, for which the needles were inserted 3 cm apart from the points of energy. Acupuncture reduced Chronic Pelvic Pain by 66% after therapy and Dyspareunia was reduced by 65%. Acupuncture confers beneficial and long-lasting effects, even 2 months after therapy. Sousa et al. 2016 6. Randomized controlled trial 40 women were who practiced yoga (n = 28), or who did not practice yoga (n = 12) 90min scheduled yoga sessions twice a week for 8 weeks. The degree of daily pain was significantly lower among the women who practiced yoga compared with the non-yoga group (p = 0. 0007). Mean(SD) baseline pain score were 60. 80 (15. 59), 58. 71 (15. 41) for yoga group andnon yoga group. Post therapymean pain score 32. 39 (21. 95) 55. 05 (21. 49) foryoga group and non-yoga group Goncalves et al. 2016 7. Retrospective study Two hundred seven gluten-free diet in After 12 months of gluten diet, 75%reported Marziali M et International Journal of Clinical Obstetrics and Gynaecology https://www.gynaecologyjournal.com ~ 889 ~ patients with severe painful endometriosis- related symptoms a follow-up of 12 months statistically significant change in painful symptoms(P<0. 005). al. 2012 8. . Randomized comparative trial. 307 patients with laparoscopically diagnosed endometriosis 3. 6-mg depot of goserelin monthly subcutaneously or oral danazol200 mg three times a day administered for 24 weeks. No statistically significant difference between the groups in terms of percentage of pregnancies nor mean time to conception. Ofthe 47 pregnant patients who had received goserelin, 34 (72. 3%) had live births; ofthe 18 danazol-treated patients, 14 (77. 8%) had live births. Shaw et al 1992 9. Retrospective comparative study 134 patients with ovarian endometriosis Diphereline, 3. 75 mg/ampoule and control In infertile patients with ovarian endometriosis GnRH- a combined with transvaginal ultrasound-guided cyst aspirationcan obtain better clinical pregnancy rate47. 76% than control group 39. 21% (p= 0. 031)It also reduced abortion rate to 6. 25% than 22. 50%in control group(p= 0. 049.) Guo et al. 2012 10. Pilot clinical study 795 Women with endometriosis or without endometriosis 0. 03 mg of ethinyl estradiol (EE) 0. 125 mg of levonorgestrel 6 to 8 weeks of continuous use of oral contraception (OC) before assisted reproduction treatment (ART) maintains ART outcomes comparable with the outcomes of age-matched controls without endometriosis. Clinical pregnancy rate in control (without endometriosis) was 35% and after treating with OC in endometrioma patients it was 41. 4%. Ziegler, et al. 2010 11. Randomized, controlled prospective study 341 infertile women 20 to 39 years of age with minimal or mild endometriosis. laparoscopic surgery Laparoscopic resection or ablation of minimal and mild endometriosis enhancespregnancy rate by 20%. Rates of fecundity were 2. 3 per 100 person-months, P=0. 006 Marcoux S, et al. 1997 12. A prospective, randomized study 100 patients with endometriomas who had either infertility or pelvic pain. laparoscopic ovarian cystectomy versus fenestration and coagulation Laparoscopic cystectomy of endometriomas is a better choice than fenestration and coagulation because the former technique leads a higher cumulative pregnancy rate (59. 4%) than the latter(23. 3%). Alborzi et al. 2004 13. Prospective, randomized clinical trial. Sixty-four patients with advanced stages of endometriosis. Cystectomy versus drainage and coagulation The median interval between the operation and the recurrence of moderate to severe pelvic pain was longer in cystectomy than in diagnostic laparoscopy (19 months versus 9. 5 months). The 24-month cumulative pregnancy rate was higher in cystectomy group than in diagnostic laparoscopy(66. 7% versus 23. 5%). Beretta et al. 1998 14. Prospective Randomized trial. 103 couples in whom minimal or mild endometriosis Ovarian stimulation and IUI using ≥75 IU FSH Treatment with superovulation and lUI was associated with superior outcome both by crude live-birth rates (11% in treatment group vs 2%inno-treatmentgroup. Tummon et al. 1997 15. Randomized, prospective trial 298 couple with 1unexplained fertility or surgically corrected endometriosis. CC 50 mg oral and IUI Clomiphene citrate (CC) and intrauterine insemination (lUI) results in increased fecundity (0. 095 vs 0. 033)when compared with periovulatory intercourse in couples with either unexplained infertility or surgically corrected endometriosis. Deaton, M. 1990 16. Prospective study 140 patients with endometriosis undergoing IVF treatment IVF Our findings demonstrate that the presence and severity of endometriosis do not influence IVF outcomes. The pregnancy rates per transfer were comparable among the groups: 39% for male factor infertility, 48% for unexplained infertility, 45% for tubal factor infertility, and 40% for endometriosis patients. Geber at al 1995 Emerging therapies: The predominant medical therapies for endometriosis are suppressive rather than curative , with symptoms reappearing upon withdrawal of medication; hence , there is a need for innovative advancements in this field . Elagolix, an oral anti -gonadotrophic drug , is a unique and promising therapy approach for endometriosis , appearing to prevent disease progression and greatly alleviate pain [6]. Resveratrol is a natural molecule with anti -angiogenic, anti- carcinogenic, pro-apoptotic, anti-oxidative, and anti - inflammatory properties , potentially offering new therapeutic avenues for endome triosis therapy [90]. Research indicates that antioxidants, including melatonin , vitamins E and C , may be beneficial to existing endometriosis treatments [91]. Furthermore, stem cell-based therapy have also demonstrated it’s potential for the management of endometriosis . Stem cell treatment for endometriosis entails the administration of stem cells to areas impacted by the condition , aiming to substitute a dysfunctional or nonviable endometrial cell population with its normal or restorative counterparts [92]. Stem cell treatment is a compelling therapeutic option for endometriosis due to its immunomodulatory and tropic effects on inflammatory lesion sites. Stem cell treatment is a potential alternative for the regeneration of damaged endometrial tissue . This therapy has generated discussion over the role of stem cells in the disease's etiology [93]. Mesenchymal ste m cell therapy have shown promising results and utilized in the treatment of infertility for International Journal of Clinical Obstetrics and Gynaecology https://www.gynaecologyjournal.com ~ 890 ~ women with premature ovarian failure and Asherman’s syndrome [94]. Preclinical studies indicate that angiogenesis in endometriotic lesions can be suppressed by inhibiting the recruitment of endothelial pr ogenitor cells (EPCs) to these lesions. Adipose derived cells caused s significant reduction in size and proliferative activity of endometriotic lesions and improved pregnancy outcomes [95].

Endometriosis is a chronic condition that significantly affects women's lives and necessitates a lifelong care strategy . The explanations behind endometriosis -related infertility remain incompletely elucidated , and this disease is multifaceted in nature. Pain and inflammation associated with endometriosis , altered pelvic architecture and adhesions , impaired ovarian function, and decreased endometrial receptivity significantly contribute to infertility in women with endometriosis. Identifying innovative , non-invasive diagnostic tools for endometriosis that also predict an increased risk of infertility is a primary research and clinical priority; delayed diagnosis facilitates disease progression , which is detrimental to fertility . Treatment options for endometriosis -related pain should be selected based on efficacy , potential adverse effects , acceptability, adherence, cost, and patient preferences . The predominant medicinal treatments for endometrio sis are suppressive rather than curative , with symptoms recurring upon withdrawal of medication; hence , there is an obligation for innovative advancements in this field. Surgery and ART remain the mainstay of effective therapy of infertility associated with endometriosis. There is need of a multidisciplinary , tailored, collaborative, and comprehensive strategy based on the patient's particular characteristics, endometriosis subtype, and degree of impairment. Conflict of Interest Not available. Financial Support Not available.

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